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In the Genes

Oncologists are looking to the data to sort indolent prostate cancers from aggressive ones. Plus: analyzing genetic testing results to see whose tumor might benefit from targeted therapies, why immunotherapy is a model for how precision medicine can work, the liquid biopsy and more.

By Doug Birch and Jim Duffy

Photo Credit: Mike Ciesielski

Urologist H. Ballentine Carter is leading efforts to prevent overtreatment for prostate cancer.

Going Deeper

Sorting patients with indolent versus aggressive prostate cancers requires understanding the differences between ethnic and racial subgroups, among other factors, notes urologist Kenneth Pienta, scientific director of the Precision Medicine Center of Excellence for Prostate Cancer, a signature initiative of Johns Hopkins inHealth. He is engaged in a study that looks at why African-Americans are far more likely than other men to develop prostate cancer in the first place and why their tumors tend to be more aggressive.

Environmental and behavioral factors probably play a role, but there appears to be a genetic link as well, says Pienta, who is hunting for the genes that might help explain why one race appears to be more at risk. “We’re looking at the entire genome to determine if there are differences,” he says.

In 2015, Pienta and other researchers published a paper reporting that African-Americans tend to have prostate tumors that grow deeper inside their prostates than in other patients and that traditional needle biopsies may too often miss them. “The tumor has to get bigger before it gets found,” he says. As a result of the study, Johns Hopkins physicians today are taking deeper prostate biopsy samples from African-American patients to ensure they get the proper diagnosis and treatment. “It’s definitely changed the way we give our care,” Pienta says. Doug Birch

Avoiding Surgery in Prostate Cancer

Sorting indolent cancers from aggressive ones.

By: Doug Birch

Every year, about 90,000 men in the United States are diagnosed with early-stage prostate cancer. In 40,000 to 50,000 of those cases, the tumors are indolent rather than aggressive—meaning they are not spreading quickly and do not immediately require surgery that can leave patients impotent or incontinent.

But distinguishing indolent tumors from their aggressive cousins is tricky, and doctors err on the side of over treatment. About half of men nationwide who don’t need prostate surgery have it anyway. Meanwhile, patients with aggressive prostate cancers may get a battery of treatments—surgery, chemotherapy, hormone therapy, radiation—when all they really needed was one.

More than a decade ago, H. Ballentine Carter, director of adult urology and one of the most sought-after prostate surgeons in the country, launched an active surveillance program at Johns Hopkins for men with prostate cancer who might otherwise face surgery.

Over the past 20 years, about 1,600 men have enrolled in this program, one of the world’s largest.

When the active surveillance program began, Carter says, all that was available was an off-the-shelf approach. “If you got into the surveillance program, then we monitored everyone exactly the same,” he says, including by conducting annual biopsies and frequent blood testing for prostate-specific antigen (PSA).

But even intensive surveillance can’t always sort indolent from aggressive tumors. To help more men avoid surgery, Carter embarked on a collaboration with Johns Hopkins biostatisticians Scott Zeger, Mufaddal Mamawala and Rebecca Yates Coley, a postdoctoral research fellow at the Bloomberg School of Public Health.

Together, they created a web application using PSA levels measured over time, prostate volumes, prior biopsy results, age and other data to calculate each patient’s risk of developing aggressive disease. It is one of the first projects coming out of Johns Hopkins inHealth.

The application—derived from 20 years of data collected from hundreds of patients—produces easy-to-interpret, color-coded charts that show the odds that a particular patient’s tumor will become severe, what future diagnostic blood tests are likely to show and the probability that the next biopsy will find evidence of a more dangerous tumor.

Says Carter, “You can tell an individual, ‘Well, even though we found more cancer on this particular biopsy, based on our models for men with similar prostate cancers as yours, it doesn’t look like you’re at greatly increased risk.’” For such patients, the prospect of delaying surgery—or even avoiding it altogether—is a welcome one indeed.

Where ‘Actionable Is the Buzzword’

When it comes to making progress against cancer, patients and their families tend toward impatience. The careful, considered approach that is a hallmark of academic medicine can seem an agonizingly slow process to people worried that time is running short for themselves or a loved one.

As precision medicine moves from the concept phase into the clinical realm, this tension can add complexity, even confusion, to decisions about treatment. Consider the hypothetical case of a patient with metastatic breast cancer facing a challenging prognosis. She comes across an article in a magazine touting the promise of genetic testing but then hears her oncologist say that such tests are not yet ready for prime time. Perhaps she checks with her insurance company, too, only to learn that the tests are not yet reimbursable for patients in her situation.

Then the woman sees an online ad from a private company offering to run a genetic screen on her tumor. The going rate for such tests is in the range of $2,000 to $4,000, a price tag that includes a report identifying potential treatments that might work against one or another of the genetic anomalies that pop up in her screen.

The patient asks her oncologist to order one of the tests. When the results come back, however, that oncologist may or may not be up to speed on the latest developments regarding the experimental treatments listed as possibilities.

Enter the multidisciplinary tumor review board at Johns Hopkins, which meets on Monday mornings at 11 a.m. Headed by Josh Lauring, an oncologist who specializes in the genetics of cancer cells, the group convenes in the David H. Koch Cancer Research Building on Orleans Street to review reports from cases just like this one.

In addition to experts in oncology and genetics, the tumor board—known as GAITWAY, for Genetic Alteration in Tumors with Actionable Yields—includes molecular pathologists, genetic counselors, a patient advocate and other specialists. The oncologist seeking the board’s advice is welcome to participate as well.

The board’s job is to identify those cases for which this brand of precision medicine might be able to make a difference here in the present, rather than off in the future.

“Actionable is the buzzword,” Lauring says. “Is there really a gene in this report that we know we can target effectively? Is there a drug that’s available now? Or an open clinical trial that’s a good fit? Or is the evidence still pretty weak? Is there nothing in the report that really reaches that bar of actionable?”

Lauring is the second chair of GAITWAY. The board was founded about four years ago by medical oncologist Ben Park, in response to one of his first encounters with a case along these lines. He was asked by a clinical oncologist to consult on a case after a genetic test on the patient’s tumor came back with a potential treatment option aimed at a particular gene. The therapy had been recommended by one of these private-sector reports.

“Our lab had helped to discover the gene that recommendation was based on, and I didn’t think it ranked as a mutation of functional consequence in cases like hers,” Park says. The patient almost died after choosing the therapy regimen recommended in that report over more proven alternatives, he reports.

“That case really showed me the danger out there of patients and oncologists acting on these reports without having the full knowledge to really evaluate all of the information,” he says.

Most of GAITWAY’s cases arrive from oncologists within the Johns Hopkins system looking for expert advice, but a number come from community oncologists as well. Lauring estimates that the board is now endorsing a treatment option in about 15 to 20 percent of cases. He is hopeful that percentage will grow in the years to come, as new cancer-related genetic anomalies come to light and new drugs are developed.

“We tend to be pretty conservative in our interpretations,” Lauring says. “We are looking for cases where the evidence of potential benefit is really strong.” Too often, the results under review are based on early-stage research done only in animal models or test tubes.

Both Park and Lauring say that their experience with GAITWAY has served to lessen their initial skepticism over private-sector testing.

“We do see cases where the evidence is strong, and some of those patients have gone on a new therapy and had really nice responses,” Lauring says. “It’s not a large number at this point, but it seems clear to me that there is a lot of promise here for the future.”

Park now serves as a paid consultant for Foundation Medicine Inc., a leading private-sector provider of genetic tests for cancer patients. That role grew out of his efforts early on to alert the company to potential problems with the information in their reports. “The good companies in this field seek out expertise and welcome help like that,” he says. “Some of them really want to do things the right way.”

One benefit of private-sector testing is sheer numbers. In an effort to build up the kind of database that can fuel advances in personalized cancer care, Foundation Medicine Inc. recently agreed to donate nearly 20,000 genetic sequencing cases to the Cancer Genome Atlas, which is maintained by the National Institutes of Health as part of a larger project, the Genomic Data Commons.

“Eventually, I do feel like a lot of this work we do interpreting actionable mutations will become routine,” Park says. “Until then, groups like Josh’s tumor board need to be a part of the process and serve like an expert second opinion.”

Immunotherapy: A Model for How Precision Medicine Can Work

By: Doug Birch

For decades, it was an intriguing idea. why not use the body’s finely tuned immune system and its arsenal to battle cancer? The hope was that if the body’s own disease-fighting cells could be turned against tumors, these cancer fighters could provide a safe, efficient and tightly focused alternative to surgery, chemotherapy and radiation treatments. But the hunt was long and frustrating, attracting a relatively small number of scientists to the field.

Fortunately, in those early years, there were just enough successes in small numbers of patients to keep researchers plugging away. “For the most part, immunotherapy strategies didn’t help the majority of patients, but there were always a few patients who had a strong response, with their cancer disappearing and their response lasting for years, so I would say this kept hope alive,” says Suzanne Topalian, a physician-scientist and director of the Melanoma Program at the Johns Hopkins Kimmel Cancer Center. She also serves as an associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy.

Then came the discovery in 2001 that cancer cells have proteins on their surface that signal immune cells to call off their attack. In recent years, Johns Hopkins has been a leader in the development of so-called checkpoint blockade drugs that block these chemical signaling pathways and strip tumors of their ability to hide from immune cells.

“The pace of discovery, development and FDA approval is accelerating in this field, which is why there is so much excitement about it,” Topalian says.

Today, the list of cancers being treated by the technique is long and rapidly growing. In just the past two years, the FDA has approved immunotherapy treatments for six different cancers: nonsmall cell lung cancer, the most common type; melanoma; kidney cancer; Hodgkin’s lymphoma; bladder cancer; and head and neck cancer.

Now, Johns Hopkins researchers are hunting for biomarkers on cancer cells that can help identify patients who will benefit from existing immunotherapy drugs. Those same biomarkers can then become the targets for new drugs.

“We come up with ideas in the lab, and they go into clinical trials,” Topalian says. “We then take biopsies and blood specimens from patients who are being treated in those clinical trials. We bring them back to the lab to try and find biomarkers that correlate either with response or resistance to the therapy. And that generates the next cycle of treatments that we test in the clinic. That’s a continuous, ongoing cycle.”

Johns Hopkins researchers are now trying to find ways to expand on the success of this approach, including by incorporating immunotherapy into multidrug treatments.

“The key point is that combination immunotherapies need to be based on scientific evidence coming from research labs rather than just taking two drugs off the shelf and saying, ‘Let’s see what happens when we combine them,’” Topalian says. “Because there are now so many possible combinations, we would never have the resources and time to test every one.” Doug Birch

The ‘Liquid Biopsy’

As advances in precision medicine are making clear, drugs and therapies increasingly require highly specific tests to predict whether they will work in a given patient.

Toward that end, researchers at Johns Hopkins, notably neurosurgeon Chetan Bettagowda, have been pioneering the development of the “liquid biopsy”—a reliable biomarker that can detect the presence or absence of cancer cells in the body by way of a simple blood test. It has been described as today’s “holy grail” in cancer therapy.

In breast cancer, such a tool would enable physicians to identify the patients who are cancer-free—and who may not need surgery after chemotherapy, for one example, or chemotherapy after surgery, for another, notes medical oncologist Ben Park, who is launching a national trial to investigate these very applications.

“That’s the biggest unmet need in oncology right now,” Park says, pointing out that perhaps 30 of every 100 post-surgical breast cancer patients are at a high risk for relapse. Right now, oncologists are giving post-surgical chemotherapy to all 100 of those patients because they are unable to identify the high-risk cases in advance.

Cancer cells shed detritus into the bloodstream during their lifetimes, and the test under review would seek out and find that detritus, or report back that there is no detritus to be found.

“It looks really promising,” Park says, “and it fits in nicely with these conversations about individualized medicine. What we’re trying to do is get to a point where we can say, ‘You don’t need to get everything and the kitchen sink. You just need to get what your individual cancer case needs so that it’s cured—not too little, not too much.’

“So while a lot of personalized medicine looks to be kind of far off in the future,” he continues, “there are places—like with this biomarker, I hope—where I think we can get there soon and make a huge impact.”

And depending on how well they work, liquid biopsies could eventually be used for annual cancer screenings. Jim Duffy

Photo credit: Justin Tsucalas

Josh Lauring heads the multidisciplinary tumor board known as GAITWAY, one of several tumor boards at Johns Hopkins.

Illustration credit: Andre DaLoba

A Foot in Both Worlds

Four years after they helped sequence the first cancer genome in 2006, two Johns Hopkins physician-researchers, Victor Velculescu and Luis Diaz, co-founded the Baltimore-based company Personal Genome Diagnostics, or PGDx, as a spinoff of their work.

“Every cancer is different,” says Velculescu, co-director of cancer biology at the Johns Hopkins Kimmel Cancer Center. “It became obvious you had to understand what is going on in an individual cancer in order to get the patient on the right therapy.”

Over the past six years, the company, which in part uses technology licensed from Johns Hopkins, has attracted $21 million in venture capital and grown from a one-room operation into a 100-employee company. PDGx today is a major provider of gene testing services to cancer researchers, drug developers, physicians and patients all over the world.

In recent months, PGDx has begun rolling out its liquid biopsy tests, which are designed to help doctors adjust treatment as a patient’s cancer mutates.

“The [cancer] genome is not static; it’s actually dynamic,” Velculescu says. “It’s evolving in the face of this therapy, and it’s important to know how it’s changing because that can tell you why it’s become resistant.” Doug Birch

Drilling Down

Among cancer researchers, there is growing recognition that the genetic forces involved in cancer growth can cut across what were once regarded as distinct types of the disease.

As an example, cancer geneticist Josh Lauring points to the gene HER2, present in perhaps 15 percent of all breast cancer cases. But HER2 also pops up with much less frequency in other types of cases, such as head and neck cancer. Can trastuzumab and other drugs that have been so successful for breast cancer patients also keep HER2 at bay with cancers elsewhere in the body?

The preliminary answer seems to be yes, at least in some cases, Lauring says. Now, there are two large national trials underway to explore how this approach can work for certain types of patients. The Johns Hopkins Kimmel Cancer Center is among the 900 sites feeding cases into one of those studies, a National Cancer Institute (NCI) initiative called Molecular Analysis for Therapy of Choice, or MATCH.

With NCI MATCH, thousands of cancer patients will be screened with a tumor biopsy, which will undergo gene sequencing that will look for changes in 143 genes. Patients who have a genetic abnormality that matches one of the drugs in the trial will be eligible to join the treatment portion of NCI MATCH. Perhaps most notable is that patients with tumors that share the same genetic abnormality will receive the drug that targets that abnormality—regardless of tumor type. Jim Duffy